成纤维细胞-心肌细胞相互作用在 HFpEF 和高血压性心脏病中心房功能障碍中的作用。
The role of fibroblast - Cardiomyocyte interaction for atrial dysfunction in HFpEF and hypertensive heart disease.
机构信息
Department of Internal Medicine and Cardiology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburgerplatz 1, 13353 Berlin, Germany; DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany.
DZHK (German Centre for Cardiovascular Research), partner site Hamburg, Germany; Universitäres Herzzentrum Hamburg, Klinik für Allgemeine und Interventionelle Kardiologie, 20246 Hamburg, Germany.
出版信息
J Mol Cell Cardiol. 2019 Jun;131:53-65. doi: 10.1016/j.yjmcc.2019.04.016. Epub 2019 Apr 18.
AIMS
Atrial contractile dysfunction is associated with increased mortality in heart failure (HF). We have shown previously that a metabolic syndrome-based model of HFpEF and a model of hypertensive heart disease (HHD) have impaired left atrial (LA) function in vivo (rat). In this study we postulate, that left atrial cardiomyocyte (CM) and cardiac fibroblast (CF) paracrine interaction related to the inositol 1,4,5-trisphosphate signalling cascade is pivotal for the manifestation of atrial mechanical dysfunction in HF and that quantitative atrial remodeling is highly disease-dependent.
METHODS AND RESULTS
Differential remodeling was observed in HHD and HFpEF as indicated by an increase of atrial size in vivo (HFpEF), unchanged fibrosis (HHD and HFpEF) and a decrease of CM size (HHD). Baseline contractile performance of rat CM in vitro was enhanced in HFpEF. Upon treatment with conditioned medium from their respective stretched CF (CM-SF), CM (at 21 weeks) of WT showed increased Ca transient (CaT) amplitudes related to the paracrine activity of the inotrope endothelin (ET-1) and inositol 1,4,5-trisphosphate induced Ca release. Concentration of ET-1 was increased in CM-SF and atrial tissue from WT as compared to HHD and HFpEF. In HHD, CM-SF had no relevant effect on CaT kinetics. However, in HFpEF, CM-SF increased diastolic Ca and slowed Ca removal, potentially contributing to an in-vivo decompensation. During disease progression (i.e. at 27 weeks), HFpEF displayed dysfunctional excitation-contraction-coupling (ECC) due to lower sarcoplasmic-reticulum Ca content unrelated to CF-CM interaction or ET-1, but associated with enhanced nuclear [Ca]. In human patients, tissue ET-1 was not related to the presence of arterial hypertension or obesity.
CONCLUSIONS
Atrial remodeling is a complex entity that is highly disease and stage dependent. The activity of fibrosis related to paracrine interaction (e.g. ET-1) might contribute to in vitro and in vivo atrial dysfunction. However, during later stages of disease, ECC is impaired unrelated to CF.
目的
心房收缩功能障碍与心力衰竭（HF）死亡率增加有关。我们之前已经表明，基于代谢综合征的 HFpEF 模型和高血压性心脏病（HHD）模型在体内（大鼠）存在左心房（LA）功能障碍。在这项研究中，我们假设，与三磷酸肌醇信号级联相关的左心房心肌细胞（CM）和心脏成纤维细胞（CF）旁分泌相互作用对于 HF 中心房机械功能障碍的表现至关重要，并且定量心房重构与疾病高度相关。
方法和结果
在 HHD 和 HFpEF 中观察到差异重塑，表现为体内心房大小增加（HFpEF）、纤维化不变（HHD 和 HFpEF）和 CM 大小减小（HHD）。在体外，HFpEF 大鼠 CM 的基础收缩性能增强。在用各自拉伸 CF（CM-SF）的条件培养基处理后，WT 的 CM（在 21 周时）表现出与旁分泌活性的肌醇 1,4,5-三磷酸诱导的 Ca 释放相关的 Ca 瞬变（CaT）幅度增加。与 HHD 和 HFpEF 相比，WT 的 CM-SF 和心房组织中的内皮素（ET-1）和肌醇 1,4,5-三磷酸诱导的 Ca 释放的旁分泌活性增加了 ET-1 的浓度。在 HHD 中，CM-SF 对 CaT 动力学没有明显影响。然而，在 HFpEF 中，CM-SF 增加了舒张 Ca 并减缓了 Ca 清除，这可能导致体内失代偿。在疾病进展期间（即 27 周时），HFpEF 由于与 CF-CM 相互作用或 ET-1 无关但与增强的核 [Ca] 相关的肌浆网 Ca 含量降低而表现出功能失调的兴奋-收缩偶联（ECC）。在人类患者中，组织 ET-1 与动脉高血压或肥胖无关。
结论
心房重构是一种复杂的实体，高度依赖于疾病和阶段。与旁分泌相互作用相关的纤维化活性（例如 ET-1）可能有助于体外和体内心房功能障碍。然而，在疾病的后期阶段，ECC 受损与 CF 无关。
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